The present invention relates to medical uses of 7-amino-3-benzyl-1-phenylpyrido[2,3-d]pyrimidin-2,4-dione derivatives as a therapeutic agent for dermatitis, particularly as a therapeutic agent for atopic dermatitis.
Dermatitis, which usually has the same meaning as eczema, is an inflammation reaction of the skin to various external and internal causes and is the most common disease among the skin diseases. Typical clinical features in acute stage dermatitis include swelling erythema, followed by the formation of papules and serous papules on the erythema. After the formation of vesicles in the skin, pustules form, followed by the erosion, crusting and desquamation of the skin. Only then does the skin begin to heal. When dermatitis turns chronic, thickening, lichenification and pigmentation of the skin all result and, in most cases, accompanied by itching. Histologically, dermatitis is characterized in swelling among epidermal cells (in a spongy state) during the acute stage. Contact dermatitis, atopic dermatitis, seborrheic dermatitis, nummular eczema, Vidal""s lichen, stasis dermatitis, dyshidrotic eczema, asteatosis eczema dermatitis, autosensitization eczema, etc. are included among recognized categories of dermatitis.
Although atopic dermatitis is thought to occur by atopy, i.e. by an allergic reaction in which immunoglobulin E (IgE) participates, a definite cause of its onset is still unknown. Atopic dermatitis is often accompanied by a high level of IgE in the blood and by eosinophilia.
Atopy itself belongs to a type I allergic response but, since atopic dermatitis is a reaction similar to eczema and contact dermatitis from a pathological viewpoint, the participation of a type IV allergic response (delayed type) has been suggested. It has also been suggested that a delayed type reaction accompanied by infiltration of eosinophils and lymphocytes plays an important role in the onset of atopic dermatitis and its change to chronic dermatitis. See Iwamoto, et al.: J. Leukoc. Biol., 52, pages 572-578 (1992); Frigas, et al.: J. Allergy Clin. Immunol., 77, pages 527-537 (1986), etc.
Symptoms of atopic dermatitis vary with age of the subject. At from about the second to the sixth month from birth, weeping eczema of the face appears first and then it gradually expands to the legs and arms and to the trunk. A strong itch is also characteristic. The symptoms are classified into a baby period (younger than 2 years old), an infant period (2-12 years old) and an adult period. During the baby period, the onset is mostly limited to the face but, gradually the skin of trunk becomes dry resulting in follicular papules (atopic skin). In infants and small children, the lesions become dry and thick areas form in the pits of the elbow and knee (lichenification). There are many cases where atopic dermatitis heals by about 12 years of age but when it carries over into an adult period, it becomes more severe. Even if the atopic dermatitis once attenuates in severity, recurrence and the worsening of symptoms are often seen and there are even some cases which require a long period to complete healing or else a complete healing is not achieved.
External application of a steroidal agent (ointment or the like) is the most effective therapy to date and no therapeutic method to replace it has yet been established. However, steroid preparations which are frequently used to treat dermatitis, including atopic dermatitis, are the pharmaceuticals which have a very active clinical effect and which also cause a great variety of adverse reactions. There have been various reports on the side effects of steroid preparations and, in the case of agents for external use such as ointments, direct harmful effects such as the thinning, shrinking and flushing of the skin have become a widespread social problem. The severe adverse reactions caused by steroid preparations used as remedies for dermatitis and atopic dermatitis have led to an eager demand in patients and in the medical field for safer pharmaceuticals which have fewer side effects.
The compounds which are used as a therapeutic agent for dermatitis according to the present invention are disclosed in Japanese Patent Laid-Open Publication 2000-119272 and in corresponding U.S. patent application Ser. No. 09/418982 to Ogino et al. Compounds having a pyrido[2,3-a]pyrimidine structure, have been reported as having an anti-allergic action. See Japanese Patent Laid-Open Publication Sho-63/45279 and U.S. Pat. No. 4,808,587 to Go et al. Further, compounds having a 7-aminopyrido[2,3-d]pyrimidine structure have a bronchodilating action. See Japanese Patent Publications 06-159322, 06-159323, and 06-159324 (Hei-8/3046, Hei-8/3164 and Hei-8/3165) and corresponding U.S. Pat. No. 5,776,942 to Furukawa et al.
None of the references discussed above disclose a medical use or a method for treating dermatitis or atopic dermatitis using a compound made according to the present invention. The present invention solves the above-mentioned problems by providing a therapeutic agent for dermatitis, particularly a therapeutic agent for atopic dermatitis, which is safer and which exhibits fewer adverse side-effects than existing therapeutic agents for dermatitis or atopic dermatitis.
The present inventors have carried out an intensive investigation of 7-aminopyrido[2,3-d]pyrimidine derivatives and have found that 7-amino-3-benzyl-1-phenylpyrido [2,3-d] pyrimidin-2,4-dione derivatives are highly effective as therapeutic agents for dermatitis, particularly for atopic dermatitis, and that these therapeutic agents for dermatitis cause few adverse reactions in the skin.
The present invention provides a therapeutic agent for dermatitis which contains a compound represented by the following formula (I), or a pharmaceutically acceptable salt or hydrate thereof, as an effective ingredient: 
In the formula, R is hydrogen or a halogen.
Compounds represented by the above formula (I) include the pharmaceutically acceptable salts thereof such as acid addition salts, salts with alkali metals, salts with alkaline-earth metals, salts with other metals or salts with bases.
The present invention includes any and all steric isomers such as cis-trans isomers, optical isomers, conformational isomers and hydrates of the compounds of formula (I).
A pharmaceutical composition which is used as a therapeutic agent for dermatitis according to the present invention can be prepared by combining a compound represented by the above formula (I) with a pharmaceutically acceptable carrier or diluent.
The present invention provides a therapeutic agent and a method of using a therapeutic agent which comprises 7-amino-3-benzyl-1-phenylpyrido [2,3-d]pyrimidin-2,4-dione derivatives for treating dermatitis, and particularly for atopic dermatitis. Specifically, the present invention provides a therapeutic agent for dermatitis which contains a compound represented by the following formula (I), or a pharmaceutically acceptable salt or hydrate thereof, as an effective ingredient: 
In the formula, R is hydrogen or a halogen. A xe2x80x9chalogenxe2x80x9d includes, but is not limited to, fluorine, chlorine, bromine or iodine.
Preferred embodiments of the present invention are
(1)A therapeutic agent for dermatitis containing a compound represented by the above formula (I) or a pharmaceutically acceptable salt or hydrate thereof as an effective ingredient.
(2) The therapeutic agent for dermatitis according to paragraph (1), wherein the agent is a therapeutic agent for atopic dermatitis.
(3) The therapeutic agent for dermatitis according to paragraphs (1) or (2), wherein the agent is for external use.
(4) The therapeutic agent for dermatitis according to any of paragraphs (1) to (3), wherein R is hydrogen in formula (I).
(5) The therapeutic agent for dermatitis according to any of paragraphs (1) to (3), wherein R is substituted at the o-position in formula (I).
(6) The therapeutic agent for dermatitis according to paragraph (5), wherein R is chloride.
Especially preferred compounds for use in treating dermatitis are:
7-amino-3-benzyl-1,2,3,4-tetrahydro-1-phenylpyrido[2,3-d]pyrimidin-2,4-dione (compound 1)
7-amino-3-(2-chlorobenzyl)-1,2,3,4-tetrahydro-1-phenylpyrido[2,3-d]pyrimidin-2,4-dione (compound 2)
The most preferred compound is the compound 1.
Compounds represented by the above formula (I) include the pharmaceutically acceptable salts thereof such as acid addition salts with hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, perchloric acid, thiocyanic acid, boric acid, formic acid, acetic acid, haloacetic acid, propionic acid, glycolic acid, citric acid, tartaric acid, succinic acid, gluconic acid, lactic acid, malonic acid, fumaric acid, anthranilic acid, benzoic acid, cinnamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid or sulfanilic acid; salts with alkali metal such as sodium or potassium, salts with an alkaline-earth metal such as calcium or magnesium, or salts with other metals such as aluminum; or salts with bases such as ammonia or organic amines. Those salts may be manufactured by known methods from the compounds of the present invention in a free state or may be mutually converted among the salts. The present invention includes any and all steric isomers such as cis-trans isomers, optical isomers, conformational isomers and hydrates of the compounds of formula (I).
A pharmaceutical composition which is used as a therapeutic agent for dermatitis according to the present invention can be prepared by combining a pharmaceutically effective amount of a compound represented by the above formula (I) with an appropriate pharmaceutically acceptable carrier or diluent. In manufacturing the pharmaceutical composition, any of various conventional methods may be used. Optimally, a therapeutic agent for dermatitis comprises a preparation for external use such as a liquid, suspension/emulsion, plaster, ointment, cataplasm, liniment or lotion. For prescription, the compound of the above formula (I) may be used as a pharmaceutically acceptable salt or hydrate, or it may be combined with other pharmaceutically active ingredient(s). Methods for the manufacture of preparations for external use are mentioned in detail, for example, in General Rule for Pharmaceutical Preparations, Commentary to the 13th Revision of the Japanese Pharmacopoeia (published by Hirokawa Shoten, 1996), the disclosure of which is herein incorporated by reference in its entirety.
Ointment preparations may be roughly classified into fat/oil type ointments, emulsified ointments, water-soluble ointments and suspended ointments according to the type of the base (vehicle) used therefor. An ointment may comprise, for example, fats, fatty oils, lanolin, vaseline, paraffins, waxes, resins, plastics, glycols, higher alcohols, glycerol, water, emulsifiers, suspending agents or other appropriate additives as a diluent, carrier or as a vehicle. Manufacture of an ointment comprises, for example, adding the compound of the present invention to the appropriate additives, diluents, carriers or vehicles followed by mixing to make the mixture homogeneous.
In manufacturing a cataplasm, a powder of the compound of the above formula (I) may be admixed with an essential oil component to give a muddy product. Depending upon the type and state of the disease to be treated, the ordinary skilled artisan can manufacture other types of preparations which are optimum for the desired therapy.
A therapeutic agent according to the present invention, or a pharmaceutical composition which is used as a therapeutic agent for dermatitis according to the present invention may be used to treat animal or human subjects who have been diagnosed with or who are known to be in need of treatment for dermatitis or eczema, such as one or more conditions selected from the group consisting of contact dermatitis, atopic dermatitis, seborrheic dermatitis, nummular eczema, Vidal""s lichen, stasis dermatitis, dyshidrotic eczema, asteatosis eczema dermatitis, and autosensitization eczema.
The preferred dosage of the compound of the present invention varies depending upon the subject to be administered (age, body weight, symptoms, etc. of the patient), form of the preparation, method for the administration, term for the administration, etc. For example, to achieve the desired effect, the compound of the present invention may be administered as an ointment containing, by weight based on the total weight of the ointment, from about 0.1% to about 15% of the compound of the present invention. The ointment may be applied on the affected area once to several times per day, for example, 5 or 6 times daily until the affected area heals.
Compounds represented by the above formula (I) can be manufactured by methods disclosed in: a) Japanese Patent Laid-Open Sho-63/45279, corresponding U.S. Pat. No. 4,808,587 to Go et al. and corresponding publication EP 0243311 B; b) Japanese Patent publications 06-159322, 06-159323 and 06-159324 (Hei-8/3049, Hei-8/3164, Hei-8/3165), corresponding U.S. Pat. No. 5776942 to Furukawa et al., and corresponding European patent publication EP 0696590 A; and c) Japanese Patent Laid-Open Publication 2000-119272, corresponding U.S. patent application Ser. No. 09/418982 to Ogino et al., and corresponding European patent publication EP 0994113 A or by a similar method. The disclosure of each of said Japanese and European patent publications, U.S. Pat. Nos 4,808,587 and 5,776,942, and U.S. application Ser. No. 09/418,982 to Ogino et al are each herein incorporated by reference in their entireties.
Methods for the production of the compounds of the present invention are further illustrated in detail by way of the following non limiting examples. The starting materials may be purchased from Aldrich Chemical Co., Inc.; Furuka Chemical Inc.; Lancaster Synthesis Inc.; Maybridge Chemical Co., Ltd.; or Tokyo Kasei K.K. or may be synthesized by known methods mentioned in the literature such as J. Org. Chem., 16, 1879 (1951); J. Am. Chem. Soc., 75,114 (1953); etc. In the following examples all parts, percentages and ratios are by weight, all temperatures are in xc2x0 C., and all reactions are conducted at about atmospheric pressure and at about room temperature unless indicated to the contrary: